After the strange ending of the previous game, Guybrush Tripwood discovers himself on one of the cars of an amusement park floating on the Caribbean Sea. As an experienced captain, Guybrush leads a logbook:

"For several days I have been carried by the sea. I have no command, no navigational aids, no provisions, not counting the half-eaten root-dog, and if I do not find water soon, I'm definitely finished. Only the hope of finding my love, Elaine, supports me. The search for the legendary treasure of the Great Noise brought me to such a miserable state. I thought they would bring me fame and glory. But instead I fell into the clutches of my enemy, the leech pirate zombie. I upset his insidious plan to marry Elaine, and he craved revenge. Very, very thirsty. At least one sip of fresh water, and I would have the strength to continue swimming. But I know that for miles around there is nothing but the ocean ... Oh, my dear Elaine ... am I doomed to die of hunger in this ocean ... not seeing once more your face? Is it really ...? "

Unnoticed for himself, he swims to Plunder Island, whose governor is none other than the love of his life - Elaine Marley. At this very time, the island is in the siege of the deadly enemy of Guybrush - the pirate zombie LeChaka, who still claims to the hand and heart of Elaine. Noticing Gaybrash, Lechak orders him to take him aboard and throw him in the hold to deal with him after the battle. In the hold, Guybrush is under surveillance, or rather under the sights of a fairly small pirate with a false beard named Bloody Nose. However, after talking with the pirate, Guybrush recognizes in him the peaceful cartographer Wally, whom they met in the previous game Monkey Island 2: LeChuck's Revenge. Wally also recognizes "Mr. Brush", but he is now a "vicious pirate". Using his "diabolical art of controversy," Guybrush manages to dissuade this small cartographer. Having access to the airborne gun, Tripwood shoots the boats of pirate skeletons sent by LeChuck to attack the fort. Wanting to reverse the course of the battle, Lechak takes in his hands the newest secret weapon - the flaming cannonball of Voodoo. At this moment, another cannon shot is heard in the hold, and the powerful rollback of the Gunbrush gun forces LeChuck to drop the core to his feet. So the evil pirate zombie LeChak finds its destruction.

The ship sinks, but Guybrush manages to get out of the overturned vessel, taking a huge diamond from the treasure chest of LeChac. On the beach, Guybrush meets Elaine. He asks for her hands and puts a diamond ring on her finger, not suspecting that it is cursed. Elaine turns into a golden statue. In search of a solution to the problem, Guybrush meets his old acquaintance - Voodoo-Lady. From it, he learns that to remove the charm with his beloved, he will have to find the same, but uncursed ring. Here's just one catch: who leaves unattended a gold statue on the island of pirates?

In his adventure Guybrush will visit Blood Island, Skull Island and, finally, in the lair of LeChac himself, who gathers an army of undead to capture the world. He will also meet many interesting characters, both new and already met in previous games of the series.